US2023226151A1PendingUtilityA1
Methods for Modulating Bile Acid Homeostasis and Treatment of Bile Acid Disorders and Diseases
Assignee: NGM BIOPHARMACEUTICALS INCPriority: Dec 27, 2012Filed: Jan 24, 2023Published: Jul 20, 2023
Est. expiryDec 27, 2032(~6.4 yrs left)· nominal 20-yr term from priority
G01N 33/92C12Q 1/6883C07K 14/50A61K 38/1825G01N 2500/04G01N 2800/04G01N 2800/08C12Q 2600/106C12Q 2600/136C12Q 2600/158A61P 1/12A61P 1/16A61P 3/00A61P 3/06A61P 3/10
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Claims
Abstract
The invention relates to variants and fusions of fibroblast growth factor 19 (FGF19), variants and fusions of fibroblast growth factor 21 (FGF21), fusions of FGF19 and/or FGF21, and variants or fusions of FGF19 and/or FGF21 proteins and peptide sequences (and peptidomimetics), having one or more activities, such as bile acid homeostasis modulating activity, and methods for and uses in treatment of bile acid and other disorders.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of modulating bile acid homeostasis or treating a bile-acid related or associated disorder, comprising administering a chimeric peptide sequence, comprising:
a) an N-terminal region comprising at least seven amino acid residues, the N-terminal region having a first amino acid position and a last amino acid position, wherein the N-terminal region comprises DSSPL (SEQ ID NO:121) or DASPH (SEQ ID NO:122); and b) a C-terminal region comprising a portion of SEQ ID NO:99 [FGF19], the C-terminal region having a first amino acid position and a last amino acid position, wherein the C-terminal region comprises amino acid residues 16-29 of SEQ ID NO:99 [FGF19], WGDPIRLRHLYTSG (SEQ ID NO:169), wherein the W residue corresponds to the first amino acid position of the C-terminal region, thereby modulating bile acid homeostasis or treating the bile-acid related or associated disorder.
2 . A method of modulating bile acid homeostasis or treating a bile-acid related or associated disorder, comprising administering a chimeric peptide sequence, comprising:
a) an N-terminal region comprising a portion of SEQ ID NO:100 [FGF21], the N-terminal region having a first amino acid position and a last amino acid position, wherein the N-terminal region comprises amino acid residues GQV, and wherein the V residue corresponds to the last amino acid position of the N-terminal region; and b) a C-terminal region comprising a portion of SEQ ID NO:99 [FGF19], the C-terminal region having a first amino acid position and a last amino acid position, wherein the C-terminal region comprises amino acid residues 21-29 of SEQ ID NO:99 [FGF19], RLRHLYTSG (SEQ ID NO:185), and wherein the R residue corresponds to the first position of the C-terminal region, thereby modulating bile acid homeostasis or treating the bile-acid related or associated disorder.
3 . A method of modulating bile acid homeostasis or treating a bile-acid related or associated disorder, comprising administering a chimeric peptide sequence, comprising:
a) an N-terminal region comprising a portion of SEQ ID NO:100 [FGF21], the N-terminal region having a first amino acid position and a last amino acid position, wherein the N-terminal region comprises at least 5 contiguous amino acids of SEQ ID NO:100 [FGF21] including the amino acid residues GQV, and wherein the V residue corresponds to the last amino acid position of the N-terminal region; and b) a C-terminal region comprising a portion of SEQ ID NO:99 [FGF19], the C-terminal region having a first amino acid position and a last amino acid position, wherein the C-terminal region comprises amino acid residues 21-29 of SEQ ID NO:99 [FGF19], RLRHLYTSG (SEQ ID NO:185), and wherein the R residue corresponds to the first position of the C-terminal region, thereby modulating bile acid homeostasis or treating the bile-acid related or associated disorder.
4 . The method of claim 3 , wherein the N-terminal region comprises at least 6 contiguous amino acids of SEQ ID NO:100 [FGF21] including the amino acid residues GQV.
5 . The method of claim 3 , wherein the N-terminal region comprises at least 7 contiguous amino acids of SEQ ID NO:100 [FGF21] including the amino acid residues GQV.
6 . A method of modulating bile acid homeostasis or treating a bile-acid related or associated disorder, comprising administering a peptide sequence, comprising or consisting of any of:
a) a FGF19 sequence variant having one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF19; b) a FGF21 sequence variant having one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF21; c) a portion of an FGF19 sequence fused to a portion of an FGF21 sequence; or d) a portion of an FGF19 sequence fused to a portion of an FGF21 sequence, wherein the FGF19 and/or FGF21 sequence portion(s) have one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF19 and/or FGF21, thereby modulating bile acid homeostasis or treating the bile-acid related or associated disorder.
7 . The method of claim 6 , wherein the peptide sequence has amino-terminal amino acids 1-16 of SEQ ID NO:100 [FGF21] fused to carboxy-terminal amino acids 21-194 of SEQ ID NO:99 [FGF19], or wherein the peptide sequence has amino-terminal amino acids 1-147 of SEQ ID NO:99 [FGF19] fused to carboxy-terminal amino acids 147-181 of SEQ ID NO:100 [FGF21] (M41), or wherein the peptide sequence has amino-terminal amino acids 1-20 of SEQ ID NO:99 [FGF19] fused to carboxy-terminal amino acids 17-181 of SEQ ID NO:100 [FGF21] (M44), or wherein the peptide sequence has amino-terminal amino acids 1-146 of SEQ ID NO:100 [FGF21] fused to carboxy-terminal amino acids 148-194 of SEQ ID NO:99 [FGF19] (M45), or wherein the peptide sequence has amino-terminal amino acids 1-20 of SEQ ID NO:99 [FGF19] fused to internal amino acids 17-146 of SEQ ID NO:100 [FGF21] fused to carboxy-terminal amino acids 148-194 of SEQ ID NO:99 [FGF19] (M46).
8 . The method of claim 6 , wherein the peptide sequence comprises at least one amino acid substitution to amino acid residues 125-129 of SEQ ID NO:99 [FGF19], EIRPD; at least one amino acid substitution to amino acid residues 126-128 of SEQ ID NO:99 [FGF19], IRP; or at least one amino acid substitution to amino acid residues 127-128 of SEQ ID NO:99 [FGF19], RP.
9 . The method of claim 8 , wherein the peptide sequence comprises a substitution to one of amino acid residues 127-128 of SEQ ID NO:99 [FGF19], IRP, wherein at least one amino acid substitution is R127L or P128E.
10 . The method of claim 9 , wherein the peptide sequence comprises
(SEQ ID NO: 3)
RPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSC
FLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKG
VHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDG
YNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFL
PMLPMVPEEPEDLRGHLESDMFSSPLETDSMDPFGL
VTGLEAVRSPSFEK (M3); or
(SEQ ID NO: 194)
RPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSC
FLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKG
VHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIREDG
YNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFL
PMLPMVPEEPEDLRGHLESDMFSSPLETDSMDPFGL
VTGLEAVRSPSFEK (M140).
11 . The method of claim 8 , wherein the peptide sequence further comprises at least one amino acid substitution to amino acid residues 1-124 of SEQ ID NO:99 [FGF19] and/or to amino acid residues 130-194 of SEQ ID NO:99 [FGF19].
12 . The method of claim 11 , wherein the peptide sequence is
(SEQ ID NO: 196)
RPLAFSDAGPHVHYGWGDPIRQRHLYTSGPHGLSSC
FLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKG
VHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDG
YNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFL
PMLPMVPEEPEDLRGHLESDMFSSPLETDSMDPFGL
VTGLEAVRSPSFEK (M160).
13 . The method of claim 1 , 2 , 3 or 6 , wherein the peptide sequence comprises or consists of any sequence set forth herein as M1 to M98 or M101 to M160, or SEQ ID NOs:1 to 98, 101 to 135, or 138 to 196.
14 . The method of claim 1 , 2 , 3 or 6 , wherein the peptide sequence comprises or consists of any sequence set forth in Tables 1-10.
15 . The method of claim 1 , 2 , 3 or 6 , wherein the peptide sequence comprises or consists of any sequence set forth in the Sequence Listing herein.
16 . The method of claim 1 , 2 or 6 , wherein the peptide sequence has a WGDPI (SEQ ID NO:170) sequence motif corresponding to the WGDPI sequence of amino acids 16-20 of SEQ ID NO:99 [FGF19].
17 . The method of claim 16 , wherein the peptide sequence maintains or increases an FGFR4 mediated activity.
18 . The method of claim 1 , 2 or 6 , wherein the peptide sequence has a substituted, mutated or absent WGDPI (SEQ ID NO:170) sequence motif corresponding to FGF19 WGDPI sequence of amino acids 16-20 of FGF19.
19 . The method of claim 18 , wherein the WGDPI (SEQ ID NO:170) sequence has one or more amino acids substituted, mutated or absent.
20 . The method of claim 1 , 2 or 6 , wherein the peptide sequence is distinct from an FGF 19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO:171), WGDPV (SEQ ID NO:172), WGDI (SEQ ID NO:173), GDPI (SEQ ID NO:174), GPI, WGQPI (SEQ ID NO:175), WGAPI (SEQ ID NO:176), AGDPI (SEQ ID NO:177), WADPI (SEQ ID NO:178), WGDAI (SEQ ID NO:179), WGDPA (SEQ ID NO:180), WDPI (SEQ ID NO:181), WGDI (SEQ ID NO:182), WGDP (SEQ ID NO:183) or FGDPI (SEQ ID NO:184) substituted for the FGF19 WGDPI (SEQ ID NO:170) sequence at amino acids 16-20.
21 . The method of any of claim 1 to 3 or 6 , wherein the N-terminal or C-terminal region is from about 20 to about 200 amino acid residues in length.
22 . The method of claim 1 , wherein the N-terminal region comprises amino acid residues VHYG (SEQ ID NO:101), wherein the N-terminal region comprises amino acid residues DASPHVHYG (SEQ ID NO:102), or wherein the N-terminal region comprises amino acid residues DSSPLVHYG (SEQ ID NO:103).
23 . The method of claim 22 , wherein the G corresponds to the last position of the N-terminal region.
24 . The method of claim 1 or 6 , wherein the N-terminal region comprises amino acid residues DSSPLLQ (SEQ ID NO:104), and wherein the Q residue is the last amino acid position of the N-terminal region.
25 . The method of claim 23 or 24 , wherein the N-terminal region further comprises: RHPIP (SEQ ID NO:106), where R is the first amino acid position of the N-terminal region; or HPIP (SEQ ID NO:107), where H is the first amino acid position of the N-terminal region; or RPLAF (SEQ ID NO:108), where R is the first amino acid position of the N-terminal region; or PLAF (SEQ ID NO:109), where P is the first amino acid position of the N-terminal region; or R, where R is the first amino acid position of the N-terminal region.
26 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence comprises or consists of any of M1 to M98 or M101 to M160 variant peptide sequences, or a subsequence or fragment of any of the M1 to M98 or M101 to M160 variant peptide sequences.
27 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence comprises or consists of any of:
(SEQ ID NO: 69)
RDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIKA
VALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHR
LPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETDSM
DPFGLVTGLEAVRSPSFEK (M69);
(SEQ ID NO: 52)
RDSSPLLQWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVAL
RTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLPV
SLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETDSMDPFG
LVTGLEAVRSPSFEK (M52);
(SEQ ID NO: 5)
RHPIPDSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIK
AVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEK
HRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETDS
MDPFGLVTGLEAVRSPSFEK (M5);
(SEQ ID NO: 160)
HPIPDSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIKA
VALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHR
LPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETDSM
DPFGLVTGLEAVRSPSFEK (M5-R);
(SEQ ID NO: 71)
HPIPDSSPLLQFGGQVRQRYLYTDDAQQTEAHLEIREDGTVGGAADQSPESLLQLKA
LKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFRELLLEDGYNVYQSEAHSLP
LHLPGNKSPHRDPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLSMVGPSQG
RSPSYAS (M71);
(SEQ ID NO: 72)
HPIPDSSPLLQFGGQVRQRYLYTDDAQQTEAHLEIREDGTVGGAADQSPESLLQLKA
LKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFRELLLEDGYNVYQSEAHGLP
LHLPGNKSPHRDPAPRGPARFLPLPGLPPAPPEPPGILAPQPPDVGSSDPLSMVGPSQG
RSPSYAS (M72);
(SEQ ID NO: 73)
HPIPDSSPLLQFGGQVRQRYLYTDDAQQTEAHLEIREDGTVGGAADQSPESLLQLKA
LKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFRELLLEDGYNVYQSEAHGLP
LHLPGNKSPHRDPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLSMVVQDEL
QGVGGEGCHMHPENCKTLLTDIDRTHTEKPVWDGITGE (M73);
(SEQ ID NO: 1 or 139)
RPLAFSDASPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL
LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYR
SEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLE
TDSMDPFGLVTGLEAVRSPSFEK (M1);
(SEQ ID NO: 2 or 140)
RPLAFSDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLL
EIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRS
EKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLET
DSMDPFGLVTGLEAVRSPSFEK (M2);
(SEQ ID NO: 3)
RPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL
LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYR
SEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLE
TDSMDPFGLVTGLEAVRSPSFEK (M3);
(SEQ ID NO: 48 or 6 or 148)
RDSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVA
LRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLP
VSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETDSMDPF
GLVTGLEAVRSPSFEK (M48);
(SEQ ID NO:49 or 7 or 149)
RPLAFSDSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGWDCARGQSAHSLLEI
KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSE
KHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETD
SMDPFGLVTGLEAVRSPSFEK (M49);
(SEQ ID NO: 50)
RHPIPDSSPLLQFGDQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIK
AVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYRSEK
HRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETDS
MDPFGLVTGLEAVRSPSFEK (M50);
(SEQ ID NO: 51 or 36 or 155)
RHPIPDSSPLLQFGGNVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIK
AVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEK
HRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETDS
MDPFGLVTGLEAVRSPSFEK (M51);
(SEQ ID NO: 192)
MDSSPLLQWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVA
LRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLP
VSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETDSMDPF
GLVTGLEAVRSPSFEK (M53);
(SEQ ID NO: 70)
MRDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIK
AVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEK
HRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLETDS
16MDPFGLVTGLEAVRSPSFEK (M70);
(SEQ ID NO: 193)
RPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL
LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILPDGYNVYR
SEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLE
TDSMDPFGLVTGLEAVRSPSFEK (M139);
RPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL
(SEQ ID NO: 194)
LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIREDGYNVYR
SEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLE
TDSMDPFGLVTGLEAVRSPSFEK (M140);
(SEQ ID NO: 195)
RPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL
LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILCDGYNVYR
SEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLE
TDSMDPFGLVTGLEAVRSPSFEK (M141); or
(SEQ ID NO: 196)
RPLAFSDAGPHVHYGWGDPIRQRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL
LEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYR
SEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLRGHLESDMFSSPLE
TDSMDPFGLVTGLEAVRSPSFEK (Ml60);
or a subsequence or fragment of any of the foregoing peptide sequences, or any of the foregoing peptide sequences wherein the R terminal residue is deleted.
28 . The method of claim 1 or 2 , wherein the N-terminal region comprises amino acid residues DSSPLLQFGGQV (SEQ ID NO:105), and wherein the V residue corresponds to the last position of the N-terminal region.
29 . The method of any of claim 1 to 3 or 6 , wherein amino acid residues HPIP (SEQ ID NO:107) are the first 4 amino acid residues of the N-terminal region.
30 . The method of any of claim 1 to 3 , 6 or 27 , wherein the first position of the N-terminal region is an R residue, or wherein the first position of the N-terminal region is an M residue, or wherein the first and second positions of the N-terminal region is an MR sequence, or wherein the first and second positions of the N-terminal region is an RM sequence, or wherein the first and second positions of the N-terminal region is an RD sequence, or wherein the first and second positions of the N-terminal region is an DS sequence, or wherein the first and second positions of the N-terminal region is an MD sequence, or wherein the first and second positions of the N-terminal region is an MS sequence, or wherein the first through third positions of the N-terminal region is an MDS sequence, or wherein the first through third positions of the N-terminal region is an RDS sequence, or wherein the first through third positions of the N-terminal region is an MSD sequence, or wherein the first through third positions of the N-terminal region is an MSS sequence, or wherein the first through third positions of the N-terminal region is an DSS sequence, or wherein the first through fourth positions of the N-terminal region is an RDSS (SEQ ID NO:115) sequence, or the first through fourth positions of the N-terminal region is an MDSS (SEQ ID NO:116) sequence, or the first through fifth positions of the N-terminal region is an MRDSS (SEQ ID NO:117) sequence, or the first through fifth positions of the N-terminal region is an MSSPL (SEQ ID NO:118) sequence, or the first through sixth positions of the N-terminal region is an MDSSPL (SEQ ID NO:119) sequence, or the first through seventh positions of the N-terminal region is an MSDSSPL (SEQ ID NO:120) sequence.
31 . The chimeric method of any one of claim 1 to 3 or 6 , wherein the last position of the C-terminal region corresponds to about residue 194 of SEQ ID NO:99 [FGF19].
32 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence comprises or consists of:
(SEQ ID NO: 160)
HPIPDSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSA
HSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEI
RPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEP
EDLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK;
(SEQ ID NO: 138 or 161)
DSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLL
EIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDG
YNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLR
GHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK;
(SEQ ID NO: 1 or 139)
RPLAFSDASPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCAR
GQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAF
EEEIRPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMV
PEEPEDLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK;
(SEQ ID NO: 2 or 140)
RPLAFSDSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCAR
GQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAF
EEEIRPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMV
PEEPEDLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK;
or
(SEQ ID NO: 141)
DSSPLVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHS
LLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRP
DGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPED
LRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK;
or a subsequence or fragment of any of the foregoing peptide sequences, or any of the foregoing peptide sequences wherein the R terminal residue is deleted.
33 . The method of claim 26 , 27 or 32 , wherein the subsequence or fragment thereof has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acid deletions from the amino terminus, the carboxy-terminus or internally.
34 . The method of claim 1 , 2 or 6 , wherein said N-terminal region, or said C-terminal region, comprises or consists of an amino acid sequence of about 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 60 to 70, 70 to 80, 80 to 90, 90 to 100 or more amino acids.
35 . The method of claim 3 or 6 , wherein said FGF19 sequence portion, or said FGF21 sequence portion, comprises or consists of an amino acid sequence of about 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100 or more amino acids of FGF19 or FGF21.
36 . The method of any of claim 1 to 3 or 6 , wherein said N-terminal region, or said C-terminal region, or said FGF19 sequence portion, or said FGF21 sequence portion, are joined by a linker or spacer.
37 . The method of any of claim 1 to 3 or 6 , wherein the N-terminus of the peptide sequence at comprises or consists of any of:
(amino acids 1-25 of SEQ ID NO: 160)
HPIPDSSPLLQFGGQVRLRHLYTSG (M5-R);
(amino acids 2-22 of SEQ ID NO: 6)
DSSPLLQFGGQVRLRHLYTSG (M6-R);
(amino acids 1-27 of SEQ ID NO: 7)
RPLAFSDSSPLLQFGGQVRLREILYTSG (M7);
(amino acids 2-26 of SEQ ID NO: 8)
HPIPDSSPLLQWGDPIRLRHLYTSG (M8-R);
(amino acids 2-28 of SEQ ID NO: 9)
HPIPDSSPLLQFGWGDPIRLRHLYTSG (M9-R);
(amino acids 2-28 of SEQ ID NO: 10)
HPIPDSSPHVHYGWGDPIRLRHLYTSG (M10-R);
(amino acids 1-27 of SEQ ID NO: 11)
RPLAFSDAGPLLQWGDPIRLREILYTSG (M11);
(amino acids 1-29 of SEQ ID NO: 12)
RPLAFSDAGPLLQFGWGDPIRLREILYTSG (M12);
(amino acids 1-27 of SEQ ID NO: 13)
RPLAFSDAGPLLQFGGQVRLREILYTSG (M13);
(amino acids 2-26 of SEQ ID NO: 14)
HPIPDSSPHVHYGGQVRLRHLYTSG (M14-R);
(amino acids 1-27 of SEQ ID NO: 15)
RPLAFSDAGPHVHYGGQVRLREILYTSG (M15);
(amino acids 1-27 of SEQ ID NO: 16)
RPLAFSDAGPHVHWGDPIRLRHLYTSG (M16);
(amino acids 1-27 of SEQ ID NO: 17)
RPLAFSDAGPHVGWGDPIRLRHLYTSG (M17);
(amino acids 1-27 of SEQ ID NO: 18)
RPLAFSDAGPHYGWGDPIRLRHLYTSG (M18);
(amino acids 1-27 of SEQ ID NO: 19)
RPLAFSDAGPVYGWGDPIRLRHLYTSG (M19);
(amino acids 1-27 of SEQ ID NO: 20)
RPLAFSDAGPVHGWGDPIRLRHLYTSG (M20);
(amino acids 1-27 of SEQ ID NO: 21)
RPLAFSDAGPVHYWGDPIRLRHLYTSG (M21);
(amino acids 1-27 of SEQ ID NO: 22)
RPLAFSDAGPHVHGWGDPIRLREILYTSG (M22);
(amino acids 1-27 of SEQ ID NO: 23)
RPLAFSDAGPEIHGWGDPIRLRHLYTSG (M23);
(amino acids 1-27 of SEQ ID NO: 24)
RPLAFSDAGPEIHYWGDPIRLRHLYTSG (M24);
(amino acids 1-27 of SEQ ID NO: 25)
RPLAFSDAGPHVYWGDPIRLRHLYTSG (M25);
(amino acids 1-27 of SEQ ID NO: 26)
RPLAFSDSSPLVHWGDPIRLREILYTSG (M26);
(amino acids 1-27 of SEQ ID NO: 27)
RPLAFSDSSPHVHWGDPIRLRHLYTSG (M27);
(amino acids 1-26 of SEQ ID NO: 28)
RPLAFSDAGPHVWGDPIRLREILYTSG (M28);
(amino acids 1-28 of SEQ ID NO: 29)
RPLAFSDAGPHVHYWGDPIRLREILYTSG (M29);
(amino acids 1-29 of SEQ ID NO: 30)
RPLAFSDAGPHVHYAWGDPIRLRHLYTSG (M30);
(amino acids 1-26 of SEQ ID NO: 31)
REIPIPDSSPLLQFGAQVRLRHLYTSG (M31);
(amino acids 1-26 of SEQ ID NO: 32)
REIPIPDSSPLLQFGDQVRLRHLYTSG (M32);
(amino acids 1-26 of SEQ ID NO: 33)
REIPIPDSSPLLQFGPQVRLRHLYTSG (M33);
(amino acids 1-26 of SEQ ID NO: 34)
REIPIPDSSPLLQFGGAVRLRHLYTSG (M34);
(amino acids 1-26 of SEQ ID NO: 35)
RHPIPDSSPLLQFGGEVRLRHLYTSG (M35);
(amino acids 1-26 of SEQ ID NO: 36)
REIPIPDSSPLLQFGGNVRLRHLYTSG (M36);
(amino acids 1-26 of SEQ ID NO: 37)
REIPIPDSSPLLQFGGQARLRHLYTSG (M37);
(amino acids 1-26 of SEQ ID NO: 38)
REIPIPDSSPLLQFGGQIRLREILYTSG (M38);
(amino acids 1-26 of SEQ ID NO: 39)
REIPIPDSSPLLQFGGQTRLREILYTSG (M39);
(amino acids 1-28 of SEQ ID NO: 40)
REIPIPDSSPLLQFGWGQPVRLREILYTSG (M40);
(amino acids 2-24 of SEQ ID NO: 74)
DAGPHVHYGWGDPIRLRHLYTSG (M74-R);
(amino acids 2-19 of SEQ ID NO: 75)
VHYGWGDPIRLRHLYTSG (M75-R);
(amino acids 2-10 of SEQ ID NO: 77)
RLREILYTSG (M77-R);
(amino acids 1-28 of SEQ ID NO: 9)
REIPIPDSSPLLQFGWGDPIRLREILYTSG (M9);
(amino acids 1-26 of SEQ ID NO: 8)
REIPIPDSSPLLQWGDPIRLREILYTSG (M8);
(amino acids 1-29 of SEQ ID NO: 12)
RPLAFSDAGPLLQFGWGDPIRLREILYTSG (M12);
(amino acids 1-28 of SEQ ID NO: 10)
REIPIPDSSPHVHYGWGDPIRLRHLYTSG (M10);
(amino acids 1-27 of SEQ ID NO: 13)
RPLAFSDAGPLLQFGGQVRLREILYTSG (M13);
(amino acids 1-26 of SEQ ID NO: 14)
REIPIPDSSPHVHYGGQVRLREILYTSG (M14);
amino acids 1-27 of SEQ ID NO: 43)
RPLAFSDAGPHVHYGGDIRLRHLYTSG (M43);
or
(amino acids 1-22 of SEQ ID NO: 6)
RDSSPLLQFGGQVRLREILYTSG (M6);
or any of the foregoing peptide sequences wherein the amino terminal R residue is deleted.
38 . The method of any of claim 1 to 3 or 6 , wherein the N-terminus of the peptide sequence comprises or consists of any of:
(amino acids 1-25 of SEQ ID NO: 160)
HPIPDSSPLLQFGGQVRLRHLYTSG (M5-R);
(amino acids 2-22 of SEQ ID NO: 6)
DSSPLLQFGGQVRLRHLYTSG (M6) (M6-R);
(amino acids 1-27 of SEQ ID NO: 7)
RPLAFSDSSPLLQFGGQVRLRHLYTSG (M7);
(amino acids 2-26 of SEQ ID NO: 8)
HPIPDSSPLLQWGDPIRLRHLYTSG (M8-R);
(amino acids 2-28 of SEQ ID NO: 9)
HPIPDSSPLLQFGWGDPIRLRHLYTSG (M9-R);
(amino acids 2-28 of SEQ ID NO: 10)
HPIPDSSPHVHYGWGDPIRLRHLYTSG (M10-R);
(amino acids 1-27 of SEQ ID NO: 11)
RPLAFSDAGPLLQWGDPIRLRHLYTSG (M11);
(amino acids 1-29 of SEQ ID NO: 12)
RPLAFSDAGPLLQFGWGDPIRLRHLYTSG (M12);
(amino acids 1-27 of SEQ ID NO: 13)
RPLAFSDAGPLLQFGGQVRLRHLYTSG (M13);
(amino acids 2-26 of SEQ ID NO: 14)
HPIPDSSPHVHYGGQVRLRHLYTSG (M14-R);
(amino acids 1-27 of SEQ ID NO: 15)
RPLAFSDAGPHVHYGGQVRLRHLYTSG (M15);
(amino acids 1-27 of SEQ ID NO: 16)
RPLAFSDAGPHVHWGDPIRLRHLYTSG (M16);
(amino acids 1-27 of SEQ ID NO: 17)
RPLAFSDAGPHVGWGDPIRLRHLYTSG (M17);
(amino acids 1-27 of SEQ ID NO: 18)
RPLAFSDAGPHYGWGDPIRLRHLYTSG (M18);
(amino acids 1-27 of SEQ ID NO: 19)
RPLAFSDAGPVYGWGDPIRLRHLYTSG (M19);
(amino acids 1-27 of SEQ ID NO: 20)
RPLAFSDAGPVHGWGDPIRLRHLYTSG (M20);
(amino acids 1-27 of SEQ ID NO: 21)
RPLAFSDAGPVHYWGDPIRLRHLYTSG (M21);
(amino acids 1-27 of SEQ ID NO: 22)
RPLAFSDAGPHVHGWGDPIRLRHLYTSG (M22);
(amino acids 1-27 of SEQ ID NO: 23)
RPLAFSDAGPHHGWGDPIRLRHLYTSG (M23);
(amino acids 1-27 of SEQ ID NO: 24)
RPLAFSDAGPHHYWGDPIRLRHLYTSG (M24);
(amino acids 1-27 of SEQ ID NO: 25)
RPLAFSDAGPHVYWGDPIRLRHLYTSG (M25);
(amino acids 1-27 of SEQ ID NO: 26)
RPLAFSDSSPLVHWGDPIRLRHLYTSG (M26);
(amino acids 1-27 of SEQ ID NO: 27)
RPLAFSDSSPHVHWGDPIRLRHLYTSG (M27);
(amino acids 1-26 of SEQ ID NO: 28)
RPLAFSDAGPHVWGDPIRLRHLYTSG (M28);
(amino acids 1-28 of SEQ ID NO: 29)
RPLAFSDAGPHVHYWGDPIRLRHLYTSG (M29);
(amino acids 1-29 of SEQ ID NO: 30)
RPLAFSDAGPHVHYAWGDPIRLRHLYTSG (M30);
(amino acids 1-26 of SEQ ID NO: 31)
RHPIPDSSPLLQFGAQVRLRHLYTSG (M31);
(amino acids 1-26 of SEQ ID NO: 32)
RHPIPDSSPLLQFGDQVRLRHLYTSG (M32);
(amino acids 1-26 of SEQ ID NO: 33)
RHPIPDSSPLLQFGPQVRLRHLYTSG (M33);
(amino acids 1-26 of SEQ ID NO: 34)
RHPIPDSSPLLQFGGAVRLRHLYTSG (M34);
(amino acids 1-26 of SEQ ID NO: 35)
RHPIPDSSPLLQFGGEVRLRHLYTSG (M35);
(amino acids 1-26 of SEQ ID NO: 36)
RHPIPDSSPLLQFGGNVRLRHLYTSG (M36);
(amino acids 1-26 of SEQ ID NO: 37)
RHPIPDSSPLLQFGGQARLRHLYTSG (M37);
(amino acids 1-26 of SEQ ID NO: 38)
RHPIPDSSPLLQFGGQIRLRHLYTSG (M38);
(amino acids 1-26 of SEQ ID NO: 39)
RHPIPDSSPLLQFGGQTRLRHLYTSG (M39);
(amino acids 1-28 of SEQ ID NO: 40)
RHPIPDSSPLLQFGWGQPVRLRHLYTSG (M40);
(amino acids 2-24 of SEQ ID NO: 74)
DAGPHVHYGWGDPIRLRHLYTSG (M74-R);
(amino acids 2-19 of SEQ ID NO: 75)
VHYGWGDPIRLRHLYTSG (M75-R);
(amino acids 2-10 of SEQ ID NO: 77)
RLRHLYTSG (M77-R);
(amino acids 1-28 of SEQ ID NO: 9)
RHPIPDSSPLLQFGWGDPIRLRHLYTSG (M9);
(amino acids 1-26 of SEQ ID NO: 8)
RHPIPDSSPLLQWGDPIRLRHLYTSG (M8);
(amino acids 1-29 of SEQ ID NO: 12)
RPLAFSDAGPLLQFGWGDPIRLRHLYTSG (M12);
(amino acids 1-28 of SEQ ID NO: 10)
RHPIPDSSPHVHYGWGDPIRLRHLYTSG (M10);
(amino acids 1-27 of SEQ ID NO: 13)
RPLAFSDAGPLLQFGGQVRLRHLYTSG (M13);
(amino acids 1-26 of SEQ ID NO: 14)
RHPIPDSSPHVHYGGQVRLRHLYTSG (M14);
amino acids 1-27 of SEQ ID NO: 43)
RPLAFSDAGPHVHYGGDIRLRHLYTSG (M43);
or
(amino acids 1-22 of SEQ ID NO: 6)
RDSSPLLQFGGQVRLRHLYTSG (M6);
or any of the foregoing peptide sequences wherein the amino terminal R residue is deleted.
39 . The method of claim 37 or 38 , wherein the peptide sequence further comprises the addition of amino acid residues 30-194 of SEQ ID NO:99 [FGF19] at the C-terminus, resulting in a chimeric polypeptide.
40 . The method of any of claim 37 or 38 , wherein the peptide sequence further comprises all or a portion of an FGF19 sequence set forth as: PHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADG KMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSH FLPMLPMVPEEPEDLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK (SEQ ID NO:188) positioned at the C-terminus of the peptide, or wherein the amino terminal “R” residue is deleted from the peptide.
41 . The method of any of claim 1 to 3 or 6 , wherein a subsequence of a chimeric peptide sequence or peptide sequence is administered, wherein the subsequence has at least one amino acid deletion.
42 . The method of claim 41 , wherein the subsequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acid deletions from the amino terminus, the carboxy-terminus or internally.
43 . The method of claim 6 , wherein the reference or wild type FGF19 sequence is set forth as:
(SEQ ID NO: 99)
RPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSCFLRIRADGVVDCAR
GQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAF
EEEIRPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMV
PEEPEDLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK.
44 . The method of claim 6 , wherein the reference or wild type FGF21 sequence is set forth as:
(SEQ ID NO: 100)
RHPIPDSSPLLQFGGQVRQRYLYTDDAQQTEAHLEIREDGTVGGAADQSP
ESLLQLKALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFRELL
LEDGYNVYQSEAHGLPLHLPGNKSPHRDPAPRGPARFLPLPGLPPALPEP
PGILAPQPPDVGSSDPLSMVGPSQGRSPSYAS.
45 . The method of any of claim 1 to 3 or 6 , wherein the N-terminal region first amino acid position is a “M” residue, an “R” residue, a “S” residue, a “H” residue, a “P” residue, a “L” residue or an “D” residue, or wherein the peptide sequence does not have a “M” residue or an “R” residue at the first amino acid position of the N-terminal region.
46 . The method of any of claim 1 to 3 or 6 , wherein the N-terminal region comprises any one of the following sequences: MDSSPL (SEQ ID NO:119), MSDSSPL (SEQ ID NO:120), SDSSPL (SEQ ID NO:112), MSSPL (SEQ ID NO:113), or SSPL (SEQ ID NO:114).
47 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence has reduced hepatocellular carcinoma (HCC) formation compared to FGF19, or an FGF 19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO:171), WGDPV (SEQ ID NO:172), WGDI (SEQ ID NO:173), GDPI (SEQ ID NO:174), GPI, WGQPI (SEQ ID NO:175), WGAPI (SEQ ID NO:176), AGDPI (SEQ ID NO:177), WADPI (SEQ ID NO:178), WGDAI (SEQ ID NO:179), WGDPA (SEQ ID NO:180), WDPI (SEQ ID NO:181), WGDI (SEQ ID NO:182), WGDP (SEQ ID NO:183) or FGDPI (SEQ ID NO:184) substituted for the WGDPI (SEQ ID NO:170) sequence at amino acids 16-20 of FGF19.
48 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence has greater glucose lowering activity compared to FGF19, or an FGF 19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO:171), WGDPV (SEQ ID NO:172), WGDI (SEQ ID NO:173), GDPI (SEQ ID NO:174), GPI, WGQPI (SEQ ID NO:175), WGAPI (SEQ ID NO:176), AGDPI (SEQ ID NO:177), WADPI (SEQ ID NO:178), WGDAI (SEQ ID NO:179), WGDPA (SEQ ID NO:180), WDPI (SEQ ID NO:181), WGDI (SEQ ID NO:182), WGDP (SEQ ID NO:183) or FGDPI (SEQ ID NO:184) substituted for the WGDPI (SEQ ID NO:170) sequence at amino acids 16-20 of FGF19.
49 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence has less lipid increasing activity compared to FGF19, or an FGF 19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO:171), WGDPV (SEQ ID NO:172), WGDI (SEQ ID NO:173), GDPI (SEQ ID NO:174), GPI, WGQPI (SEQ ID NO:175), WGAPI (SEQ ID NO:176), AGDPI (SEQ ID NO:177), WADPI (SEQ ID NO:178), WGDAI (SEQ ID NO:179), WGDPA (SEQ ID NO:180), WDPI (SEQ ID NO:181), WGDI (SEQ ID NO:182), WGDP (SEQ ID NO:183) or FGDPI (SEQ ID NO:184) substituted for the WGDPI (SEQ ID NO:170) sequence at amino acids 16-20 of FGF19.
50 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence has less triglyceride, cholesterol, non-HDL or HDL increasing activity compared to FGF19, or an FGF 19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO:171), WGDPV (SEQ ID NO:172), WGDI (SEQ ID NO:173), GDPI (SEQ ID NO:174), GPI, WGQPI (SEQ ID NO:175), WGAPI (SEQ ID NO:176), AGDPI (SEQ ID NO:177), WADPI (SEQ ID NO:178), WGDAI (SEQ ID NO:179), WGDPA (SEQ ID NO:180), WDPI (SEQ ID NO:181), WGDI (SEQ ID NO:182), WGDP (SEQ ID NO:183) or FGDPI (SEQ ID NO:184) substituted for the WGDPI (SEQ ID NO:170) substituted for the WGDPI sequence at amino acids 16-20 of FGF19.
51 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence has less lean mass reducing activity compared to FGF21.
52 . The method of any of claims 47 to 51 , wherein the HCC formation, glucose lowering activity, lipid increasing activity, or lean mass reducing activity is ascertained in a db/db mouse.
53 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence binds to fibroblast growth factor receptor 4 (FGFR4) or activates FGFR4, or does not detectably bind to FGFR4 or activate FGFR4.
54 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence binds to FGFR4 with an affinity less than, comparable to or greater than FGF19 binding affinity for FGFR4.
55 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence activates FGFR4 to an extent or amount less than, comparable to or greater than FGF19 activates FGFR4.
56 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or insertions.
57 . The method of claim 56 , wherein the amino acid deletions are at the N- or C-terminus, or internal.
58 . The method of claim 56 , wherein the amino acid substitution, or deletion is at any of amino acid positions 8-20 of FGF19 (AGPHVHYGWGDPI) (SEQ ID NO:187).
59 . The method of any of claim 1 to 3 or 6 , wherein the peptide sequence comprises one or more L-amino acids, D-amino acids, non-naturally occurring amino acids, or amino acid mimetic, derivative or analogue.
60 . The method of any of claim 1 to 3 or 6 , wherein the chimeric peptide sequence or peptide sequence comprises a pharmaceutical composition.
61 . The method of any of claim 1 to 3 or 6 , wherein the bile acid associated or related disorder comprises a metabolic syndrome; a lipid or glucose disorder; cholesterol or triglyceride metabolism; type 2 diabetes; cholestasis, intrahepatic cholestasis, primary biliary cirrhosis (PBC), primary familial intrahepatic cholestasis (PFIC), progressive PFIC, primary sclerosing choangitis (PSC), pregnancy intrahepatic cholestasis (PIC), neonatal cholestasis, and drug induced cholestasis, diseases of extrahepatic cholestasis, bile cut compression from tumor, bile duct blockade by gall stones, bile acid malabsorption and other disorders involving the distal small intestine, ileal resection, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, idiopathic disorders impairing absorption of bile acids, diarrhea, bile acid diarrhea (BAD), GI symptoms, GI cancers, liver cancers, biliary cancers, colon cancer, hepatocellular cancer, bile acid synthesis abnormalities, non-alcoholic steatohepatitis (NASH), cirrhosis, portal hypertension, or any combination thereof.
62 . The method of any of claim 1 to 3 or 6 , wherein the bile acid associated or related disorder comprises a lipid- or glucose-related disorder.
63 . The method of any of claim 1 to 3 or 6 , wherein the bile acid associated or related disorder comprises bile acid malabsorption or diarrhea.
64 . The method of any of claim 1 to 3 or 6 , wherein the bile acid associated or related disorder comprises cholestasis or primary biliary cirrhosis.
65 . The method of any of claim 1 to 3 or 6 , wherein the bile acid associated or related disorder comprises primary sclerosing cholangitis.
66 . The method of any of claim 1 to 3 or 6 , wherein the bile acid associated or related disorder comprises PFIC or progressive PFIC.
67 . A method for identifying a peptide sequence having that modulates bile acid homeostasis without having substantial HCC activity, comprising:
a) providing a candidate peptide sequence; b) administering the candidate peptide sequence to a test animal; c) measuring bile acid levels of the animal after administration of the candidate peptide sequence, to determine if the candidate peptide sequence modulates bile acid homeostasis; and d) analyzing the candidate peptide sequence for induction of HCC in the animal, or expression of a marker correlating with HCC activity, wherein a candidate peptide that modulates bile acid homeostasis but does not have substantial HCC activity thereby identifies the candidate peptide sequence as a peptide sequence having that modulates bile acid homeostasis without substantial HCC activity.
68 . The method of claim 67 , wherein the test animal is a db/db mouse.
69 . The method of claim 67 , further comprising assessing a hepatic tissue sample from the test animal to determine whether the candidate peptide sequence exhibits evidence of inducing HCC.
70 . The method of claim 67 , wherein the marker correlating with HCC activity comprises lipid profile, and wherein less lipid increasing activity compared to FGF19 indicates the peptide does not have substantial HCC activity.
71 . The method of claim 67 , wherein the marker correlating with HCC activity comprises aldo-keto reductase gene expression, and wherein up-regulating or increasing aldo-keto reductase gene expression compared to FGF19 indicates that the peptide does not have substantial HCC activity.
72 . The method of claim 67 , wherein the marker indicative of HCC activity comprises Slc1a2 gene expression, and wherein down-regulating or decreasing Slc1a2 gene expression compared to FGF21 indicates that the peptide does not have substantial HCC activity.Join the waitlist — get patent alerts
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